title: Cerivastatin, genetic variants, and the risk of rhabdomyolysis.
abstract: OBJECTIVE
  The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response, rhabdomyolysis in a small proportion of users, points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis.
  
  
  METHODS
  This study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association study to identify risk factors in other regions of the genome. A total of 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies.
  
  
  RESULTS
  Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (P=0.002), but not variants in CYP2C8 (P=0.073) or UGTs (P=0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (odds ratio: 1.89; 95% confidence interval: 1.40-2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (P<0.001). The genome-wide association study identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (P=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (odds ratio: 0.48; 95% confidence interval: 0.36-0.63).
  
  
  CONCLUSIONS
  We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA. marciant@uw.edu
authors.forename: Kristin D
authors.initials: KD
authors.lastname: Marciante
authors.forename: Jon P
authors.initials: JP
authors.lastname: Durda
authors.forename: Susan R
authors.initials: SR
authors.lastname: Heckbert
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.forename: Ken
authors.initials: K
authors.lastname: Rice
authors.forename: Barbara
authors.initials: B
authors.lastname: McKnight
authors.forename: Rheem A
authors.initials: RA
authors.lastname: Totah
authors.forename: Bani
authors.initials: B
authors.lastname: Tamraz
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Kroetz
authors.forename: Hisayo
authors.initials: H
authors.lastname: Fukushima
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Kaspera
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Glazer
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Austin
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Cashell E
authors.initials: CE
authors.lastname: Jaquish
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D016022:Case-Control Studies; D065727:Cytochrome P-450 CYP2C8; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011725:Pyridines / Q000009:adverse effects* / Q000627:therapeutic use; D012206:Rhabdomyolysis / Q000139:chemically induced* / Q000235:genetics*; D012306:Risk; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D065727:Cytochrome P-450 CYP2C8; D014453:Glucuronosyltransferase; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011725:Pyridines; D019837:Ryanodine Receptor Calcium Release Channel; D000099148:UGT1A1 Enzyme; C503999:SLCO1B1 protein, human; C086276:cerivastatin; C450259:CYP2C8 protein, human; C122075:UDP-glucuronosyltransferase, UGT1A3